Role of the 5-HT2A receptor in acute effects of LSD on empathy and circulating oxytocin

Psychedelic lysergic acid diethylamide (LSD) has re-emerged in psychiatric research and is being tested in Phase II trials for conditions such as anxiety and depression. Earlier work has established that the acute subjective psychedelic effects of LSD are primarily mediated via the serotonin 5-HT2A receptor, because these effects are largely blocked by the 5-HT2A antagonist ketanserin. LSD also produces socioemotional effects—such as increased closeness, trust and emotional empathy—and modestly raises plasma oxytocin, a peptide implicated in emotion processing. However, whether LSD’s empathy-enhancing and oxytocin-releasing effects vary across doses and whether they are mediated by 5-HT2A receptor activation remained unclear. Holze and colleagues designed the present study to address those gaps. The investigators tested graded oral doses of LSD (0, 25, 50, 100 and 200 µg) on emotional empathy using the Multifaceted Empathy Test (MET) in healthy volunteers, and they examined the contribution of 5-HT2A receptors by administering ketanserin (40 mg) prior to the highest LSD dose (200 µg). Plasma oxytocin and LSD concentrations, and subjective drug effects, were also measured to relate physiological and subjective responses to empathic performance.

The study used a double-blind, placebo-controlled, random-order crossover design with six 25-h test sessions per participant: placebo, 25 µg LSD, 50 µg LSD, 100 µg LSD, 200 µg LSD, and 200 µg LSD after pretreatment with ketanserin 40 mg. Block randomisation balanced condition order and washout periods were at least 10 days. A double-dummy method ensured blinding: participants received two capsules and two solution administrations each session to match active and placebo dosing. Ketanserin or placebo capsules were given at 08:00 and LSD or placebo solution at 09:00; sessions began at 07:45. Sixteen healthy adults (eight men, eight women; mean age 29 ± 6.4 years) participated. Exclusion criteria included significant psychiatric history, recent or heavy illicit drug use, use of interfering medications, pregnancy, and major physical illness. Urine drug and pregnancy tests were performed at screening and before sessions. Participants remained in a controlled hospital room with an investigator present for up to 24 h after dosing. Primary behavioural assessment was the Multifaceted Empathy Test (MET), administered 6 h after LSD dosing to avoid peak cognitive impairment. The computerised MET comprises 120 trials: 40 photographs used to assess explicit emotional empathy (how much the participant feels for the person) and implicit emotional empathy (arousal elicited by the scene) rated on 1–9 scales, and cognitive empathy scored as percent correct on a four-choice recognition task. Subjective ‘‘any drug effect’’ was measured with a 0–100 mm visual analogue scale (VAS). Blood samples were collected for plasma oxytocin at 1, 3 and 8 h after dosing and for plasma LSD concentrations at multiple time points; oxytocin was assayed by ELISA and LSD by ultra‑high performance liquid chromatography tandem mass spectrometry. Statistical analyses used repeated-measures ANOVA to test dose-response effects (drug as within-subjects factor), followed by Tukey post hoc tests when main effects were significant. Separate ANOVAs compared placebo, LSD and LSD + ketanserin conditions. The significance threshold was p < 0.05.

Emotional empathy: Repeated-measures ANOVA revealed significant main effects of LSD on both explicit and implicit emotional empathy (explicit: F4,44 = 4.64, p < 0.01; implicit: F4,44 = 4.82, p < 0.01), indicating a dose-dependent increase. Post hoc comparisons showed that only the highest 200 µg dose produced significant increases versus placebo for explicit (p < 0.05) and implicit (p < 0.01) empathy. Cognitive empathy was not altered by LSD (data not shown). Effect of ketanserin: When comparing placebo, 200 µg LSD and 200 µg LSD with ketanserin pretreatment, there were significant main effects on explicit and implicit empathy (explicit: F2,28 = 4.53, p < 0.05; implicit: F2,28 = 8.56, p < 0.01). Post hoc tests indicated that both LSD alone and LSD + ketanserin increased explicit (LSD p < 0.05; LSD + ketanserin p = 0.09) and implicit (LSD p < 0.001; LSD + ketanserin p < 0.01) empathy compared with placebo. Overall, ketanserin did not significantly reduce the LSD-induced increases in emotional empathy. Subjective drug effects: LSD produced dose-dependent subjective effects on the VAS for ‘‘any drug effect.’’ At 6 h—when the MET was performed—subjective effects had declined to approximately half-maximal levels. Oxytocin: Significant main effects on plasma oxytocin were observed at 1 h and 3 h after dosing (F2,28 = 7.00, p < 0.01 and F2,28 = 4.21, p < 0.05, respectively). Post hoc tests showed that only LSD alone increased oxytocin at 1 h (p < 0.01) and showed a trend at 3 h (p = 0.06) versus placebo, and that oxytocin at 1 and 3 h was higher after LSD alone compared both with placebo (1 h p < 0.01) and with LSD + ketanserin (1 h p < 0.01; 3 h p < 0.05). Thus, ketanserin prevented the LSD-induced increase in circulating oxytocin. Plasma LSD concentrations: At the time of the MET (6 h), mean plasma LSD concentrations were 2.2 ± 1.0 ng/ml after 200 µg LSD and 2.5 ± 0.9 ng/ml after 200 µg LSD + ketanserin. Peak (Emax) concentrations reported were 3.9 ± 0.8 ng/ml for 200 µg LSD and 4.4 ± 0.8 ng/ml for 200 µg LSD + ketanserin.

Holze and colleagues interpret the findings as evidence that a high single dose of LSD (200 µg) enhances both explicit and implicit emotional empathy in healthy volunteers, confirming previous reports with LSD and similar effects seen with psilocybin and MDMA on the MET. The investigators note that only the highest dose produced statistically reliable increases at the 6 h testing point used in this study. With respect to mechanism, the authors highlight a dissociation: ketanserin, which strongly attenuates LSD’s subjective psychedelic effects, did not meaningfully block the empathy-enhancing effects, suggesting that those empathogenic effects may not critically depend on 5-HT2A receptor activation. The discussion raises 5-HT1A receptors as potential mediators because LSD binds to 5-HT1A and ketanserin does not block that receptor; prior pharmacological evidence linking 5-HT1A to emotion processing is cited as contextual support. By contrast, the LSD-induced increase in circulating oxytocin was prevented by ketanserin, indicating that oxytocin release in response to LSD depends on 5-HT2A receptor stimulation. The magnitude of oxytocin elevation after LSD was modest (1.25–3-fold) relative to the larger increases typically seen after MDMA (3–11-fold), implying different mechanisms underpin oxytocin release for the two drugs. The authors further propose that LSD-induced oxytocin release might be indirect—that is, secondary to the subjective, autonomic or stress-related responses to a strong psychedelic experience—because oxytocin increases were absent when subjective effects were blocked by ketanserin. Strengths noted include the well-characterised investigational product, a within-subjects double-blind multi-dose design that included an ‘‘active’’ low-dose control, and the paired receptor-blocking manipulation. Key limitations acknowledged are the small sample size of 16 participants (albeit with 96 sessions in total), measurement of oxytocin only for the 200 µg dose, and the timing of the MET at 6 h after dosing rather than at peak effects; consequently, the authors concede that lower doses such as 100 µg might also enhance empathy at earlier peak times but this was not tested. They also caution that findings come from healthy volunteers in a controlled laboratory setting and may not generalise to recreational use or to patient populations. Finally, the authors suggest clinical relevance: enhanced emotional empathy may be therapeutically beneficial and could contribute to broader therapeutic processes observed with psychedelics and MDMA, but whether LSD produces similar empathy changes in patients with social or empathy deficits, and whether such changes mediate clinical benefit, remains to be investigated.